Field
The present invention relates to a novel catalytic hydrogenation of substituted 2-methyl cyanopyridyl derivatives, wherein the substitution is present on the pyridine ring, in particular 3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [=Py-CN] to the corresponding substituted 2-ethylaminopyridine derivatives, in particular 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine [=Py-ethanamine] or salts thereof in the presence of metal catalysts such as in particular Raney catalysts.
Description of Related Art
Substituted 2-methyl cyanopyridyl derivatives, wherein the substitution is present on the pyridine ring, such as in particular 3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile are important intermediates for the preparation of Fluopyram (N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide), a commercially available fungicide, according to formula (Ia) shown below

The production of Fluopyram is disclosed in WO-A 2004/16088.
In general the catalytic hydrogenation of nitriles is well known in the literature and can be carried out with different catalysts under either acidic, basic or also neutral conditions (Nishimura in “Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis”, pp. 254-285, John Wiley and Sons, New York, 2001). It is also known that the catalytic hydrogenation of nitriles to the desired primary amines is usually accompanied by the formation of significant amounts of secondary and tertiary amines which contaminate the desired primary amine and makes the isolation very complicated, costly and inefficient and thus not suitable for being used on an industrial scale.
The catalytic hydrogenation of a substituted 2-methyl cyanopyridyl derivative to a substituted 2-ethylaminopyridine derivative according to formula (III) or its corresponding ammonium salt under hydrogen pressure in the presence of a metal catalyst in a protic solvent is described in WO 2004/016088 and EP-A 1674455. WO-A 2004/016088 and EP-A 1 674 455 disclose concretely the catalytic reduction of [3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [Py-CN] into [3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine [Py-ethanamine] in the presence of a palladium catalyst on charcoal in a protic solvent being acetic acid. The method described in WO-A 2004/016088 and EP-A 1 674 455 has the drawback in that the yield of the hydrogenation reaction of [Py-CN] followed by hydrolysis of the N-acetyl intermediate to [Py-ethanamine] is low. Another difficulty with this process is the potential for catalyst deactivation by the large amount of side products formed which could amount up to 60% of the end product. Side products include but are not limited to dechlorinated compounds, in particular of 2-[5-(trifluoromethyl)pyridin-2-yl]ethanamine. The low selectivity to the desired product and the formation of different side products makes the economic isolation of the compound according to formula (III) not acceptable at an industrial scale.
Raney catalysts, which are also called activated metal catalysts, comprise an alloy of at least one catalytically active metal and at least one metal that can be leached with a base. In a lot of cases aluminum is used for the alkali-soluble alloy component, but other metals such as zinc, silicium, molybdenum or chromium can also be used. By adding alkalis to the alloy the leachable component is dissolved out, due to which the catalyst becomes activated. The temperature used to leach the alloy leading to a three-dimensional mesh-like structure having pores of different sizes providing the catalyst with high thermal and structural stability and the capacity to absorb hydrogen into the pores. Examples of Raney catalysts are Raney nickel catalysts or Raney cobalt catalysts which are based on nickel alloys or cobalt-aluminium alloys which are activated in the presence of strong base like NaOH. In addition Raney catalysts are economically of interest and more readily available as they are easier to produce than supported catalysts.
It is known in the prior art to improve the hydrogenation of nitriles to the corresponding amines in the presence of an acylating agent. For example, EP-A 1 674 455 discloses a two-step synthesis of substituted 2-ethylaminopyridine derivatives comprising the catalytic reduction of reaction of a 2-methylcyanopyridine derivative in the presence of an acylating agent and of a catalyst, in a solvent, under a hydrogen pressure to provide the respective 2-ethylaminopyridyl derivative.
The catalytic hydrogenation step is performed in the presence of an excess of four equivalents of acetanhydride (Ac2O). After hydrolysis of the intermediate the desired product was formed with significant amounts of side product. In addition, this method does not disclose any workup procedure nor recycling process of the expensive palladium catalyst. In addition, the reaction mixture contains large amounts of hydrochloric acid and is therefore highly corrosive. The solvent methanol reacts with the hydrochloric acid forming the gas chlormethane which is toxic and needs to be separated. Consequently the process described is disadvantageous from the economic, environmental and safety standpoint.
WO 2004/041210 relates to compounds, which are useful in the treatment of bacterial infections. Therein, the preparation of a substituted pyridinyl carbamate is mentioned, comprising the step of reacting a substituted pyridinyl acetonitrile compound to the corresponding substituted pyridinyl amine compound in THF under addition of BH3-THF and HCl, followed by NaOH addition and extraction with EtOAc. However, therein no presence of a metal catalyst, particularly no palladium catalyst, is mentioned. WO 2008/125839 relates to specific pyrimidine compounds and the pharmaceutical use thereof. Therein, the preparation of 2-(6-methyl-pyridin-2-yl) ethanamine from the corresponding pyridine-2-yl acetonitrile in THF under addition of borane dimethyl sulfide complex in THF and subsequent addition of HCL is mentioned. However, therein no presence of a metal catalyst, particularly no palladium catalyst, is mentioned.
WO 2011/047156 relates to small molecule heterocyclic inhibitors of sepiapterin reductase and the medical use thereof. Therein, the reaction of a chlorine substituted pyridinyl acetonitrile compound to the corresponding chlorine substituted pyridinyl ethanamine compound in THF under addition of BH3-DMS. However, therein neither acid addition nor the presence of a metal catalyst, particularly no palladium catalyst, is mentioned.
Skerlj et al. (Journal of Organic Chemistry, Vol. 67, No. 4, 2002, pages 1407-1410) relates to the synthesis of azamacrocyles, wherein the ring nitrogens are regioselectively functionalized. Therein, an organozinc palladium catalysed coupling with a functionalized bromopyridine is carried out. However, therein only a borane reduction followed by a so-called Nehishi coupling but no catalytic hydrogenation is carried out. In any case, the borane reduction reaction as described therein is not suitable in large scale production as it makes use and leads to undesired reaction products and is expensive.
None of the described prior art processes is suitable for a large scale production. In contrast, the new process of the present invention, as described in detail hereinafter, provides an economic process with significantly reduced formation of unwanted toxic side-products, particularly with reduced formation of unwanted dehalogenated side-products, and increased yield of the desired reaction products.
The chemoselective catalytic hydrogenation of nitriles according to formula (II) as disclosed below wherein at least one of the X substituents is halogen is in general problematic. Such compounds are easily dehalogenated during the catalytic hydrogenation thus forming undesired dehalogenated side-products.
A respective 2-methyl cyanopyridyl derivative according to formula (II), wherein at least one X substituent is halogen, preferably chlorine, can be defined by the following formula (II′) below. Upon dehalogenation during the catalytic hydrogenation process, the corresponding dehalogenated compounds of formula (II″), as defined below, can be formed.
Halogen substituted corresponding dehalogenated compoundcompound(preferably chlorine substituted (preferably dechlorinated compound)compound)  p = 1, 2, 3 or 4p = 1, 2, 3 or 4each substituent X is chosen, each substituent X is chosen, independently of theindependently of theothers, as being hydrogen, others, as being hydrogen, halogen, C1-C4 alkyl orhalogen, C1-C4 alkyl orC1-C4 haloalkyl with the C1-C4 haloalkyl with the proviso that at least oneproviso that the at leastsubstituent X is halogen, one halogen substituent, preferably chlorinepreferably chlorinesubstituent, of the corresponding compound (II′)is replaced by hydrogen
The tendency of a halogen-containing compound to dehalogenate during catalytic hydrogenation is higher for bromine—than for chlorine-containing compounds and higher for two- or more fold substituted compounds than for onefold substituted compounds. (cf. Nishimura in “Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis”, pp. 623-637, John Wiley and Sons, New York, 2001). A large number of methods with different additives have been developed to reduce the hydrodehalogenation of aromatic compounds. Most of these additives have drawbacks such as low chemoselectivity, undesired side products, costs and toxicity.
It is therefore an object of the present invention to provide a novel, safer, more economically and environmentally viable process suitable for industrial scale for preparing substituted 2-ethylaminopyridine derivatives of the formula (III) from substituted 2-methyl cyanopyridyl derivatives of the formula (II), as defined below.